Microbiota-mediated fibrotic remodeling in the inflamed intestine

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ABSTRACT Fibrotic disorders are associated with an estimated 45% of human deaths. Chronic inflammation-associated intestinal fibrosis is a significant complication in ~40% of Crohn’s disease (CD) patients. This condition causes severe intestinal thickening and blockage, and is the most common reason for bowel resection in CD patients. Despite this public health problem, there is minimal understanding behind the disease process of CD- associated fibrogenesis. The microbiota provides a putative causal link to CD and other inflammatory bowel diseases, but it remains unknown which specific microbial products induce distinct cellular responses and host phenotypes. We hypothesize that a class of secreted microbial small molecules from a dysbiotic microbiota disrupts local host metal homeostasis and promotes inflammation-associated fibrosis by altering macrophage function. Nutrient metals are essential for living organisms, and the intestine is a battleground where host and resident microbes fight to acquire metal. Host metal scavenging and sequestration defends against infectious diseases, but its contribution to chronic inflammation-associated disease is not well understood. Here we reveal a novel inflammation-associated fibrosis model using gnotobiotic Il10-/- mice mono-colonized with adherent-invasive Escherichia coli (AIEC) NC101. Fibrosis requires bacterial production of a specific small molecule metallophore that is over-represented in AIEC strains and abundant in the metagenomes of CD patients. Surprisingly, fibrosis does not require bacterial uptake and utilization of the metallophore, suggesting it targets the host. Indeed, this metallophore induces metal-starvation genes in macrophages. Metallophores are abundant in the gut microbiota, with hundreds predicted in the metagenomes of the Human Microbiome Project (HMP). Therefore, our project has broad implications and supports a model in which excessive metal chelation may characterize a dysbiotic microbiota that favors fibrotic vs. non-fibrotic CD. Iron and zinc deficiency are associated with CD and promote fibrosis in animal models of extra-intestinal fibrosis. Accordingly, the objective of this project is to define mechanisms by which microbial metallophores promote fibrogenesis, and link microbial metal scavenging and altered host metal homeostasis with CD-associated fibrosis. We have generated numerous AIEC strains that abolish the synthesis and/or transport of metallophores. We will utilize these strains and purified metallophores in our novel inflammation-associated fibrosis mouse model, an essential tool that recapitulates the histologic and molecular features of CD- associated fibrosis. We will define the metal specificity underlying the pro-fibrotic in vivo effects using NC101 and clinical strains. We will also identify the pro-fibrotic colonic monocyte/macrophage population and explore mechanisms by which altered metal availability promotes this macrophage phenotype. Understanding precisely how specific bacterial products impact distinct host disease phenotypes is essential for developing microbiota-based diagnostics and therapeutics for inflammatory bowel diseases.